Membrane transport and intracellular metabolism of folate compounds have been extensively studied in bacteria and in animal cell lines, but these processes are poorly characterized in human cells. I suggest that a better understanding of these cellular functions might provide new insights into several clinical problems. For example, my preliminary work suggests that disorders of cellular folate metabolism rather than simple vitamin deficiency, may cause or contribute to the hematologic abnormalities in some patients with preleukemic conditions such as aplastic anemia, sideroblastic anemia and erythremic myelosis. One objective of this proposed research is to identify these patients and characterize their cellular metabolic abnormality. Patients with these preleukemic conditions will be screened for evidence of impaired folate metabolism by measuring uptake of radiolabeled folate in erythrocytes, peripheral blood lymphocytes, and bone marrow cells. Identified patients will be studied in more detail for defects of membrane transport or intracellular utilization of the vitamin. Following treatment with high doses of folic acid, an attempt will be made to assess whether this therapy alters the risk of subsequent leukemic transformation. In conjunction with these patient studies, I plan to more fully characterize the membrane transport system for folate compounds in human cells, using erythrocytes as a model system. A better understanding of this cellular function may facilitate the design of more effective chemotherapeutic regimens utilizing folate antagonists. Finally, these studies may also provide new approaches to the treatment of malaria, since these intra-erythrocytic parasites depend upon the host cell membrane for transport of nutrients. I intend to investigate the anti-malarial activity of compounds which inhibit the membrane transport of folate compounds.